A large number of heritable traits are not amenable to pedigree analysis because of incomplete penetrance, the requirement for a environmental factor, or the infeasibility of collecting genotypic data from relatives of affected individuals. Such traits must be localized by population-genetic-association studies. However, the detection of polymorphic genes that influence quantitative traits, disease states, and other characters by association analysis depends on the persistence of measurable linkage disequilibrium (i.e., haplotype-allele association). An approach to the maximization of the linkage-disequilibrium for gene-localization studies involves mapping by admixture linkage disequilibrium (MALD), whereby populations composed of recently mixed ethnic groups display transient linkage disequilibrium over longer centimorgan (cM) intervals for at least 20 generations as compared to the panmictic founder populations from which the admixed ethnic group was derived. Theoretical and simulation studies that predict the limits of population parameters influencing MALD assessment have been described by this and other laboratories. A MALD map was produced for 744 short tandem repeat polymorphisms (STR) distributed throughout the human genome containing assessments of allele frequencies in African Americans, Asians, European Americans, and Hispanics. This allele frequency data was used to compute differences in composite delta, log-likelihood ratios, and I* between ethnic groups. This should allow the selection of markers suitable for case-control disease association studies in admixed populations such as African Americans or Hispanics since high values of these measures increase the likelihood of detecting association between a marker and a disease locus. We have observed linkage disequilibrium (LD) in African Americans between the FY locus on chromosome 1 and flanking STR markers as well as with AT3, a diallelic polymorphism located over 20 cM from FY. The sign of the disequilibrium coefficient between the FY and AT3 was consistent with admixture LD since the alleles found to be in positive association (i.e., the corresponding haplotypes occurred at a frequency significantly greater than the product of the corresponding allele frequencies) were from the same ancestral populations. We now have found linkage disequilibrium in African Americans between the GC locus on chromosome 4 and flanking STRs demonstrating that admixture LD is a general phenomenon.
| Smith, Michael W; Patterson, Nick; Lautenberger, James A et al. (2004) A high-density admixture map for disease gene discovery in african americans. Am J Hum Genet 74:1001-13 |
